Abstract：
:Alzheimer's Disease (AD) is a highly complex disease involving a broad range of clinical, cellular, and biochemical manifestations that are currently not understood in combination. This has led to many views of AD, e.g. the amyloid, tau, presenilin, oxidative stress, and metal hypotheses. The amyloid hypothesis has dominated the field with its assumption that buildup of pathogenic β-amyloid (Aβ) peptide causes disease. This paradigm has been criticized, yet most data suggest that Aβ plays a key role in the disease. Here, a new loss-of-function hypothesis is synthesized that accounts for the anomalies of the amyloid hypothesis, e.g. the curious pathogenicity of the Aβ42/Aβ40 ratio, the loss of Aβ caused by presenilin mutation, the mixed phenotypes of APP mutations, the poor clinical-biochemical correlations for genetic variant carriers, and the failure of Aβ reducing drugs. The amyloid-loss view accounts for recent findings on the structure and chemical features of Aβ variants and their coupling to human patient data. The lost normal function of APP/Aβ is argued to be metal transport across neuronal membranes, a view with no apparent anomalies and substantially more explanatory power than the gain-of-function amyloid hypothesis. In the loss-of-function scenario, the central event of Aβ aggregation is interpreted as a loss of soluble, functional monomer Aβ rather than toxic overload of oligomers. Accordingly, new research models and treatment strategies should focus on remediation of the functional amyloid balance, rather than strict containment of Aβ, which, for reasons rationalized in this review, has failed clinically.
journal_name
Prog Neurobioljournal_title
Progress in neurobiologyauthors
Kepp KPdoi
10.1016/j.pneurobio.2016.06.004subject
Has Abstractpub_date
2016-08-01 00:00:00pages
36-60eissn
0301-0082issn
1873-5118pii
S0301-0082(16)30036-3journal_volume
143pub_type
杂志文章,meta分析,评审abstract：:Reorganization of the somatotopic map in the spinal dorsal horn may be elicited by a variety of deafferenting lesions, including transection of peripheral nerves or dorsal roots, or the application of neurotoxins. While such lesions give rise to a variety of neurochemical and morphological changes in the dorsal horn, ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/0301-0082(95)00040-2
更新日期：1996-02-01 00:00:00
abstract：:Any biological structure can be studied using mutations that interfere either with its emergence or its function. We investigate spontaneous and induced mutations in the mouse that affect neuromuscular development and function. The wobbler mouse (phenotype WR, genotype wr/wr) suffers from muscular atrophy because of t...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/0301-0082(94)90071-x
更新日期：1994-02-01 00:00:00
abstract：:This article reviews a series of experiments aimed at investigating the reciprocal trophic interactions which regulate the normal morphofunctional features and the plasticity of the adult rodent climbing fibre-Purkinje cell system. Climbing fibre deprivation induces profound functional and structural changes in the Pu...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：
更新日期：1995-11-01 00:00:00
abstract：:The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neuron...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2011.10.001
更新日期：2012-05-01 00:00:00
abstract：:Studies of neuropeptide and peptide hormone signaling are coming of age in Drosophila due to rapid developments in molecular genetics approaches that overcome the difficulties caused by the small size of the fly. In addition we have genome-wide information on genes involved in peptide signaling, and growing pools of p...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2010.04.010
更新日期：2010-09-01 00:00:00
abstract：:Japanese encephalitis (JE) is one of the most important endemic encephalitis in the world especially in Eastern and Southeastern Asia. JE affects over 50,000 patients and results in 15,000 deaths annually. JE virus is a single stranded positive sense RNA virus belonging to family flaviviridae. JE virus is transmitted ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2010.01.008
更新日期：2010-06-01 00:00:00
abstract：:An understanding of how axons elongate is needed to develop rational strategies to treat neurological diseases and nerve injury. Growth cone-mediated neuronal elongation is currently viewed as occurring through cytoskeletal dynamics involving the polymerization of actin and tubulin subunits at the tip of the axon. How...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2011.04.002
更新日期：2011-07-01 00:00:00
abstract：:Neuromuscular junctions (NMJs) have long been studied as particularly accessible examples of chemical synapses. Nonetheless, some important features of neuromuscular transmission are still poorly understood. One of these is the low statistical variability of the number of transmitter quanta released from motor nerve t...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2015.09.004
更新日期：2015-11-01 00:00:00
abstract：:Microglia, macrophages that reside in the brain, can express at least 12 different ion channels, including voltage-gated proton channels. The properties of H+ currents in microglia are similar to those in other phagocytes. Proton currents are elicited by depolarizing the membrane potential, but activation also depends...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(00)00062-9
更新日期：2001-06-01 00:00:00
abstract：:Following rapid methodological advances, ultra-high field (UHF) functional and anatomical magnetic resonance imaging (MRI) has been repeatedly and successfully used for the investigation of the human auditory system in recent years. Here, we review this work and argue that UHF MRI is uniquely suited to shed light on h...
journal_title：Progress in neurobiology
pub_type： 杂志文章
doi：10.1016/j.pneurobio.2020.101887
更新日期：2020-08-01 00:00:00
abstract：:Brain sex differences are programmed largely by sex hormone secretions and direct sex chromosome effects in early life, and are subsequently modulated by early life experiences. The brain's resident immune cells, called microglia, actively contribute to brain development. Recent research has shown that microglia are s...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2018.09.002
更新日期：2019-05-01 00:00:00
abstract：:The cause of sleep is a complex question, which needs first, a clear distinction amongst the different meanings of a causal relationship in the study of a given behavior, second, the requisites to be met by a suggested cause, and third, a precise definition of sleep to distinguish behavioral from polygraphic sleep. Th...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(00)00013-7
更新日期：2000-11-01 00:00:00
abstract：:At the psychological level, the notion that emotional events may be better remembered is a long accepted view. Its translation into neurobiological mechanisms has led to the proposal of the 'emotional tag' concept, according to which, the activation of the amygdala by emotionality would result in modulation of neural ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2011.03.004
更新日期：2011-06-01 00:00:00
abstract：:Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic cells in the locus coeruleus (LoC). Release of noradrenaline by attentional/arousal/vigilance factors appears to be essential for learning and is responsible for the consolidation of memory. Noradrenaline can activate any ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(02)00023-0
更新日期：2002-08-01 00:00:00
abstract：:The cloning of K(Ca)2 channels revealed three subtypes, with each displaying distinct but partially overlapping expression distributions in the mammalian CNS and periphery. Activation of K(Ca)2 channels leads to membrane hyperpolarization and inhibition of action potential firing. Block of K(Ca)2 channels has been sug...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2010.03.002
更新日期：2010-07-01 00:00:00
abstract：:The proteolytical processing of the amyloid precursor protein (APP) gives rise to beta-amyloid peptides, which accumulate in brains of Alzheimer's disease (AD) patients. Different soluble or insoluble higher molecular weight forms of beta-amyloid peptides have been postulated to trigger a complex pathological cascade ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2006.06.001
更新日期：2006-06-01 00:00:00
abstract：:This review describes the role of the pedunculopontine nucleus (PPN) in various functions, including sleep-wake mechanisms, arousal, locomotion and in several pathological conditions. Special emphasis is placed on the auditory input to the PPN and the possible role of this nucleus in the manifestation of the P1 middle...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/0301-0082(95)00023-o
更新日期：1995-10-01 00:00:00
abstract：:Cysteine string protein (CSP) was discovered by use of a synapse-specific, monoclonal antibody to screen a cDNA expression library in Drosophila. A vertebrate CSP homolog was later identified and shown to co-purify with synaptic vesicles. CSP-α is now recognized as a membrane constituent of many regulated secretory or...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2020.101758
更新日期：2020-05-01 00:00:00
abstract：:The K+-Cl- co-transporter KCC2 is a neuron-specific, Cl- extruder that uses K+ gradient for maintaining low intracellular [Cl-]. It is indeed well established that sustaining an outwardly-directed electrochemical Cl- gradient across the neuronal membrane is fundamental for a proper function of postsynaptic GABAA recep...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2017.11.002
更新日期：2018-03-01 00:00:00
abstract：:The Midline Glia of Drosophila are required for nervous system morphogenesis and midline axon guidance during embryogenesis. In origin, gene expression and function, this lineage is analogous to the floorplate of the vertebrate neural tube. The expression or function of over 50 genes, summarised here, has been linked ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(00)00016-2
更新日期：2000-12-01 00:00:00
abstract：:Aging of the human brain is associated with "normal" functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodeg...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2010.11.006
更新日期：2011-02-01 00:00:00
abstract：:This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitocho...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2011.10.007
更新日期：2012-01-01 00:00:00
abstract：:Auditory verbal hallucinations (AVH) occur in psychotic disorders, but also as a symptom of other conditions and even in healthy people. Several current theories on the origin of AVH converge, with neuroimaging studies suggesting that the language, auditory and memory/limbic networks are of particular relevance. Howev...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2016.11.002
更新日期：2017-01-01 00:00:00
abstract：:Brain lactate formation, intercellular exchange and utilization has been implicated in memory formation. However, the individual role of either neuronal or astroglial monocarboxylate transporters for the acquisition and consolidation of information remains incomplete. Using novel transgenic mice and a viral vector app...
journal_title：Progress in neurobiology
pub_type： 杂志文章
doi：10.1016/j.pneurobio.2020.101888
更新日期：2020-11-01 00:00:00
abstract：:Recently, opioid receptor like1 (ORL1) receptor was identified. The ORL1 receptor is a G protein coupled receptor and the sequence of the ORL1 receptor is closely related to that of the opioid receptors. Nociceptin/orphanin FQ has been identified as a potent endogenous agonist of the ORL1 receptor and the sequence of ...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(98)00067-7
更新日期：1999-04-01 00:00:00
abstract：:This review summarizes recent work on the use of reporter genes to label selected neuronal populations in transgenic mice, with particular emphasis on gonadotropin-releasing hormone (GnRH) neurons. Reporter genes discussed are the lacZ, green fluorescent protein (GFP), luc, and bla genes, which encode the reporter pro...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(00)00038-1
更新日期：2001-04-01 00:00:00
abstract：:Cells in the nervous system can respond to different kinds of stress, e.g. injury, with production and release of inflammatory molecules, including cytokines. One of the most important proinflammatory cytokines is interleukin-1, affecting most organs of the body. The high constitutive expression of interleukin-1 in th...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2009.10.015
更新日期：2010-02-09 00:00:00
abstract：:Gene expression patterns in neurons are complex and are modulated in response to multiple extracellular stimuli. In addition, during development and as neurons differentiate into distinct neuronal phenotypes, there is a co-ordinated activation and repression of a variety of genes. It is becoming increasingly evident t...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/s0301-0082(96)00041-x
更新日期：1996-11-01 00:00:00
abstract：:High frequency oscillations (HFO) have a variety of characteristics: band-limited or broad-band, transient burst-like phenomenon or steady-state. HFOs may be encountered under physiological or under pathological conditions (pHFO). Here we review the underlying mechanisms of oscillations, at the level of cells and netw...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2012.02.005
更新日期：2012-09-01 00:00:00
abstract：:The spectrum of inflammatory diseases is nowadays considered to include diverse diseases of the central nervous system (CNS). Current evidence suggests that syndromes such as Alzheimer's disease (AD) have important inflammatory and immune components and may be amenable to treatment by anti-inflammatory and immunothera...
journal_title：Progress in neurobiology
pub_type： 杂志文章,评审
doi：10.1016/j.pneurobio.2003.08.001
更新日期：2003-08-01 00:00:00
